Esser MJ, Sawynok J: Acute amitriptyline in a rat model of neuropathic pain: Differential symptom and route effects

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Pain (Impact Factor: 5.21). 05/1999; 80(3):643-53. DOI: 10.1016/S0304-3959(98)00261-9
Source: PubMed


The present study was designed to determine whether amitriptyline, a prototypical tricyclic antidepressant, could produce pain relieving properties in a rat model of neuropathic pain. Nerve injury was produced by tight ligation of the lumbar 5th and 6th dorsal roots and this resulted in persistent stimulus evoked neuropathic pain symptoms (tactile allodynia and thermal hyperalgesia). Thermal hyperalgesia was measured using a focused light beam directed at the ventral surface of the paw while tactile allodynia was determined using Semmes-Weinstein monofilaments applied to the ventral surface of the paw. Amitriptyline was administered systemically (intraperitoneal), spinally (intrathecal cannula), and locally (subcutaneously) via direct injection into the dorsal surface of the paw. Following systemic administration, amitriptyline completely reversed thermal hyperalgesia (10 mg/kg) in the injured paw. Spinal administration of amitriptyline (60 microg) also produced an antihyperalgesic effect. Interestingly, local administration of amitriptyline (100 nmol) had an immediate antihyperalgesic effect that persisted for 120 min following administration. Amitriptyline had no alleviating effect against mechanical allodynia regardless of the route of administration, but curiously, produced hyperaesthesia in the contralateral paw. These results indicate that in the rat model of spinal nerve ligation, amitriptyline is effective in alleviating thermal hyperalgesia (systemically, spinally and locally) but is ineffective against mechanical allodynia. The peripheral efficacy of amitriptyline suggests the possibility of the development of cream formulations that may be able to increase the local concentration of amitriptyline without increasing the systemic dose and the subsequent occurrence of side effects.

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    • "Pharmacological Reports use of these drugs that have local analgesic effects has been proposed [9] [10] [11] [12] [13] [14], but there is little data regarding antidepressant topical coadministration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies. Tricyclic antidepressants are the most studied group of antidepressants for the treatment of neuropathic pain. "
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    ABSTRACT: Background: The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies. Methods: This study was performed on rats after chronic constriction injury (CCI) to the sciatic nerve. The von Frey and Hargreaves' tests were used to assess mechanical allodynia and thermal hyperalgesia, respectively, after intraplantar (ipl) or subcutaneous (sc) administration of amitriptyline, doxepin, or venlafaxine, or their ipl co-administration with morphine on day 12-16 after injury. Results: The ipl administration of amitriptyline (3, 15 mg), doxepin (1, 5, 10, 15 mg), or venlafaxine (2, 7 mg) was effective in antagonizing CCI-induced allodynia. Their sc injection at a site distal to the injured side, did not induce alterations in pain thresholds, which supports the local mode of action. Of the three antidepressants used in this study, only ipl co-administration of amitriptyline with morphine significantly enhanced its effect in contrast to doxepin and venlafaxine, both of which weakened the analgesic effect of morphine. Conclusions: In summary, the results suggest that when amitriptyline (but not doxepin or venlafaxine) is locally co-administered with morphine the effectiveness under neuropathic pain is enhanced, although additional studies are necessary to explain differential mechanisms of interaction of antidepressant drugs with morphine after local administration.
    Full-text · Article · Jun 2014 · Pharmacological reports: PR
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    • "It inhibits ectopic and bursting discharges from injured nerves and modulates activation and inactivation kinetics of sodium channels in sensory neurons [13]. In addition, systemic or intraspinal administration of amitriptyline has been demonstrated to produce an anti-hyperalgesic effects on same sensory endpoints [12,14,15]. However, the mechanism by which amitriptyline exerts its effect on the prevention of mechanical allodynia remains controversial. "
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    ABSTRACT: Amitriptyline, a tricyclic antidepressant and potent use-dependent blocker of sodium channels, has been shown to attenuate acute and chronic pain in several preclinical modes. The purpose of this study was to investigate whether intrathecal pretreatment with amitriptyline combined with post-injury intra-peritoneal amitriptyline is more effective than post-injury treatment alone on L5 spinal nerve ligation (SNL)-induced neuropathic pain. 96 adult male Sprague–Dawley rats were allocated into 4 groups: group S, Sham; group L, L5 spinal nerve L igation with vehicle treatment; group A, SNL and post-injury intra-peritoneal ( A bdominal) amitriptyline twice daily × 3 days; group P, intrathecal P retreatment with amitriptyline, SNL and intra-peritoneal amitriptyline twice daily × 3 days. Responses to thermal and mechanical stimuli, as well as sodium channel expression in injured dorsal root ganglion (DRG) and activated glial cells in spinal dorsal horn (SDH) were measured pre-operatively and on post-operative day (POD) 4, 7, 14, 21 and 28. SNL-evoked hyper-sensitivity responses to thermal and mechanical stimuli, up-regulated Nav1.3 and down-regulated Nav1.8 expression in DRG, and activated microglia and astrocytes in SDH. In group A, intra-peritoneal amitriptyline alone alleviated thermal hypersensitivity on POD7, reversed Nav1.8 and reduced activated microglia on POD14. In group P, intrathecal pretreatment with amitriptyline not only potentiated the effect of intra-peritoneal amitriptyline on thermal hypersensitivity and Nav1.8, but attenuated mechanical hypersensitivity on POD7 and reduced up-regulated Nav1.3 on POD14. Furthermore, this treatment regimen reduced astrocyte activation on POD14. Concomitant intrathecal pretreatment and post-injury intra-peritoneal amitriptyline was more effective than post-injury treatment alone on attenuation of behavioral hypersensitivity, decrease of activated microglia and astrocytes and dysregulated Nav1.3 and 1.8.
    Full-text · Article · Jun 2012 · BMC Neurology
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    • "The tricyclic antidepressant amitriptyline is widely used in the treatment of pain in man (Sindrup et al., 2005). In rodents, it produces behavioural consequences reported as anti-nociception in several models of neuropathic pain (Esser and Sawynok, 1999; Gerner et al., 2002; Lynch et al., 2005; Nagata et al., 2009; Su et al., 2009). Neuropathic pain is a complex chronic pain state as a consequence of tissue injury, and interest has focused recently on the possible relationship between endogenous ATP and P2X receptors (nomenclature follows Alexander et al., 2009) expressed by microglia in the parts of the dorsal horn where primary afferents terminate (McGaraughty and Jarvis, 2006). "
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    ABSTRACT: Amitriptyline is a tricyclic antidepressant that is also widely used to treat neuropathic pain in humans, but the mechanism of this anti-hyperalgesic effect is unknown. Microglia in the mouse spinal cord become activated in neuropathic pain, and expression of P2X4 receptors by these microglia is increased. Antisense RNA targeting P2X4 receptors suppresses the development of tactile allodynia in rats. This suggests that blockade of P2X4 receptors might be the mechanism by which amitriptyline relieves neuropathic pain. We expressed human, rat and mouse P2X receptors (P2X2, P2X4, P2X7) in human embryonic kidney cells and evoked inward currents by applying ATP. We compared the action of ATP on control cells and cells treated with amitriptyline. Amitriptyline (10 microM), either applied acutely or by pre-incubation for 2-6 h, had no effect on inward currents evoked by ATP (0.3-100 microM) at human P2X4 receptors. At rat and mouse receptors, amitriptyline (10 microM) caused a modest reduction in the maximum responses to ATP, without changes in EC(50) values, but it had no effect at 1 microM. Amitriptyline also had no effects on currents evoked by ATP at rat P2X2 receptors, or at rat or human P2X7 receptors. The results do not support the view that amitriptyline owes its pain-relieving actions in man to the direct blockade of P2X4 receptors.
    Full-text · Article · Mar 2010 · British Journal of Pharmacology
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